PROJECT SUMMARY This Imaging ? Science Track Award for Research Transition application proposes support for early stage investigator Ansel Hillmer, Ph.D., to establish a new research program in the area of brain imaging and drug abuse research. Pain relief is a commonly cited rationale for medical cannabis use, which continues to increase throughout the country. However, brain mechanisms underlying putative analgesic effects of cannabis are not well understood. Cannabis use activates cannabinoid receptors, which through cross-talk with the opioid system increases endogenous opioid peptide levels. Preclinical studies show that this endogenous opioid response to cannabis mediates analgesic properties. Yet these effects of cannabis on the opioid system have not been mapped in people. The goal of this proposed research is to establish proof of concept for a novel human imaging paradigm measuring the opioid response to smoked cannabis. The opioid response will be related with pain response to investigate a neurochemical basis of cannabis' analgesic effects. The study population will be people with experience smoking cannabis who do not meet criteria for cannabis use disorder and are otherwise healthy. This project features positron emission tomography (PET) brain imaging to measure opioid receptor availability, and the cold pressor task to measure pain response. Both measurements will be performed under two conditions; 1) baseline, and 2) after cannabis smoking. Data analyses will first determine if there are significant changes in opioid receptor availability between baseline and after cannabis smoking. The percent change in opioid receptor availability will measure opioid response. Similarly, the change in pain response between baseline and after cannabis smoking will measure analgesic effects. A second set of analyses will determine if the opioid response correlates with analgesic effects. Taken together, this experimental approach will provide a valuable tool evaluating the role of the brain's opioid system in mediating analgesic effects of cannabis smoking. This imaging paradigm will have abundant applications for subsequent research studying the neurochemical basis of cannabis use for pain relief.